CA1097653A - Process for the preparation of clavulanic acid esters - Google Patents

Process for the preparation of clavulanic acid esters

Info

Publication number: CA1097653A
Authority: CA; Canada
Prior art keywords: salt; ester; acid; base; methyl
Prior art date: 1976-12-11
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired

Application number

CA292,807A

Other languages

English (en)

French (fr)

Inventor

Thomas T. Howarth

John B. Harbridge

Roger J. Ponsford

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Beecham Group PLC

Original Assignee

Beecham Group PLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1976-12-11

Filing date

1977-12-09

Publication date

1981-03-17

1976-12-11 Priority claimed from GB51808/76A external-priority patent/GB1589367A/en

1977-12-09 Application filed by Beecham Group PLC filed Critical Beecham Group PLC

1981-03-17 Application granted granted Critical

1981-03-17 Publication of CA1097653A publication Critical patent/CA1097653A/en

Status Expired legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 184
HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical class OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 title claims abstract description 53
238000002360 preparation method Methods 0.000 title claims abstract description 33
150000003839 salts Chemical class 0.000 claims abstract description 89
150000002148 esters Chemical class 0.000 claims abstract description 78
HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims abstract description 62
239000002253 acid Substances 0.000 claims abstract description 48
229960003324 clavulanic acid Drugs 0.000 claims abstract description 41
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 40
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 39
238000006243 chemical reaction Methods 0.000 claims abstract description 33
150000001875 compounds Chemical class 0.000 claims abstract description 23
150000001450 anions Chemical class 0.000 claims abstract description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 126
-1 trimethyloxonium tetrafluoroborate Chemical compound 0.000 claims description 71
239000002585 base Substances 0.000 claims description 49
229940090805 clavulanate Drugs 0.000 claims description 32
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 29
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 26
150000003983 crown ethers Chemical class 0.000 claims description 22
239000002904 solvent Substances 0.000 claims description 22
239000011734 sodium Substances 0.000 claims description 20
229910052708 sodium Inorganic materials 0.000 claims description 19
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 17
229910003002 lithium salt Inorganic materials 0.000 claims description 17
159000000002 lithium salts Chemical class 0.000 claims description 17
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
229910052744 lithium Inorganic materials 0.000 claims description 15
125000004432 carbon atom Chemical group C* 0.000 claims description 14
125000000217 alkyl group Chemical group 0.000 claims description 12
230000007062 hydrolysis Effects 0.000 claims description 12
238000006460 hydrolysis reaction Methods 0.000 claims description 12
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 11
239000011575 calcium Substances 0.000 claims description 11
239000011591 potassium Substances 0.000 claims description 11
229910052700 potassium Inorganic materials 0.000 claims description 11
ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 11
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 10
229910052791 calcium Inorganic materials 0.000 claims description 10
239000011541 reaction mixture Substances 0.000 claims description 9
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 8
239000003729 cation exchange resin Substances 0.000 claims description 8
238000001704 evaporation Methods 0.000 claims description 8
239000011347 resin Substances 0.000 claims description 8
229920005989 resin Polymers 0.000 claims description 8
XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
239000012074 organic phase Substances 0.000 claims description 7
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 7
159000000000 sodium salts Chemical class 0.000 claims description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
239000011777 magnesium Substances 0.000 claims description 6
LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
239000000725 suspension Substances 0.000 claims description 6
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
229910052749 magnesium Inorganic materials 0.000 claims description 5
229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
239000012156 elution solvent Substances 0.000 claims description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
JMRXTGCDVQLAFM-JSYANWSFSA-M lithium;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Li+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 JMRXTGCDVQLAFM-JSYANWSFSA-M 0.000 claims description 4
239000003960 organic solvent Substances 0.000 claims description 4
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
229910052783 alkali metal Inorganic materials 0.000 claims description 3
150000001350 alkyl halides Chemical group 0.000 claims description 3
238000004108 freeze drying Methods 0.000 claims description 3
ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
239000001095 magnesium carbonate Substances 0.000 claims description 3
229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
239000000463 material Substances 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
235000017550 sodium carbonate Nutrition 0.000 claims description 3
DWCSXQCXXITVKE-UHFFFAOYSA-N triethyloxidanium Chemical class CC[O+](CC)CC DWCSXQCXXITVKE-UHFFFAOYSA-N 0.000 claims description 3
QDNCLIPKBNMUPP-UHFFFAOYSA-N trimethyloxidanium Chemical class C[O+](C)C QDNCLIPKBNMUPP-UHFFFAOYSA-N 0.000 claims description 3
KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical group CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
150000001340 alkali metals Chemical class 0.000 claims description 2
229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims description 2
125000000304 alkynyl group Chemical group 0.000 claims description 2
AZUFHGGGPUUXKI-FLFDDASRSA-N benzyl (2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound O=C([C@@H]1N2C(=O)C[C@H]2O\C1=C/CO)OCC1=CC=CC=C1 AZUFHGGGPUUXKI-FLFDDASRSA-N 0.000 claims description 2
229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
238000011065 in-situ storage Methods 0.000 claims description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
125000006501 nitrophenyl group Chemical group 0.000 claims description 2
230000020477 pH reduction Effects 0.000 claims description 2
125000005633 phthalidyl group Chemical group 0.000 claims description 2
229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
239000011736 potassium bicarbonate Substances 0.000 claims description 2
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
238000005406 washing Methods 0.000 claims description 2
239000000126 substance Substances 0.000 claims 30
159000000003 magnesium salts Chemical class 0.000 claims 9
229960003975 potassium Drugs 0.000 claims 9
235000007686 potassium Nutrition 0.000 claims 9
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 4
125000005843 halogen group Chemical group 0.000 claims 3
WOGMLDNCNBLDCA-JSYANWSFSA-M sodium;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [Na+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 WOGMLDNCNBLDCA-JSYANWSFSA-M 0.000 claims 3
NYRAVIYBIHCEGB-UHFFFAOYSA-N [K].[Ca] Chemical compound [K].[Ca] NYRAVIYBIHCEGB-UHFFFAOYSA-N 0.000 claims 2
150000001342 alkaline earth metals Chemical class 0.000 claims 2
230000003197 catalytic effect Effects 0.000 claims 2
238000007327 hydrogenolysis reaction Methods 0.000 claims 2
230000003301 hydrolyzing effect Effects 0.000 claims 2
235000014824 magnesium bicarbonate Nutrition 0.000 claims 2
235000011181 potassium carbonates Nutrition 0.000 claims 2
150000003385 sodium Chemical class 0.000 claims 2
229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
235000017557 sodium bicarbonate Nutrition 0.000 claims 2
229940001593 sodium carbonate Drugs 0.000 claims 2
NHJVRSWLHSJWIN-UHFFFAOYSA-M 2,4,6-trinitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC([N+]([O-])=O)=C(S([O-])(=O)=O)C([N+]([O-])=O)=C1 NHJVRSWLHSJWIN-UHFFFAOYSA-M 0.000 claims 1
XSGMGAINOILNJR-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methyl-3-tritylsulfanylbutanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC(C(O)=O)C(C)(C)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XSGMGAINOILNJR-UHFFFAOYSA-N 0.000 claims 1
125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
239000003513 alkali Substances 0.000 claims 1
125000003342 alkenyl group Chemical group 0.000 claims 1
239000010953 base metal Substances 0.000 claims 1
NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical group [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims 1
229910000020 calcium bicarbonate Inorganic materials 0.000 claims 1
125000001183 hydrocarbyl group Chemical group 0.000 claims 1
229910052739 hydrogen Inorganic materials 0.000 claims 1
239000001257 hydrogen Substances 0.000 claims 1
238000002955 isolation Methods 0.000 claims 1
XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims 1
QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 claims 1
239000002370 magnesium bicarbonate Substances 0.000 claims 1
229910000022 magnesium bicarbonate Inorganic materials 0.000 claims 1
LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 claims 1
239000000376 reactant Substances 0.000 claims 1
235000015424 sodium Nutrition 0.000 claims 1
229930182555 Penicillin Natural products 0.000 abstract description 2
150000002960 penicillins Chemical class 0.000 abstract description 2
239000000654 additive Substances 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
239000000203 mixture Substances 0.000 description 20
239000000047 product Substances 0.000 description 14
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
229940093499 ethyl acetate Drugs 0.000 description 9
235000019439 ethyl acetate Nutrition 0.000 description 9
VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
230000008020 evaporation Effects 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
238000006266 etherification reaction Methods 0.000 description 5
229910052938 sodium sulfate Inorganic materials 0.000 description 5
235000011152 sodium sulphate Nutrition 0.000 description 5
238000003756 stirring Methods 0.000 description 5
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
239000003921 oil Substances 0.000 description 4
235000019198 oils Nutrition 0.000 description 4
239000007787 solid Substances 0.000 description 4
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
238000004440 column chromatography Methods 0.000 description 3
239000003480 eluent Substances 0.000 description 3
239000012071 phase Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 2
101150041968 CDC13 gene Proteins 0.000 description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
235000019502 Orange oil Nutrition 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
229920001429 chelating resin Polymers 0.000 description 2
NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
239000002274 desiccant Substances 0.000 description 2
238000001035 drying Methods 0.000 description 2
IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
125000004494 ethyl ester group Chemical group 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
150000002367 halogens Chemical group 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
150000004702 methyl esters Chemical class 0.000 description 2
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
239000010502 orange oil Substances 0.000 description 2
239000012429 reaction media Substances 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
239000012258 stirred mixture Substances 0.000 description 2
238000010626 work up procedure Methods 0.000 description 2
DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
229930186147 Cephalosporin Natural products 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
241001517488 Clavus Species 0.000 description 1
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
101100536354 Drosophila melanogaster tant gene Proteins 0.000 description 1
ABXLAQVLJQLBNX-UHFFFAOYSA-N FC1(CC(B1)(F)F)F.C[O+](C)C Chemical compound FC1(CC(B1)(F)F)F.C[O+](C)C ABXLAQVLJQLBNX-UHFFFAOYSA-N 0.000 description 1
241000972349 Ocoa Species 0.000 description 1
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
239000012736 aqueous medium Substances 0.000 description 1
229910052788 barium Inorganic materials 0.000 description 1
DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
238000009835 boiling Methods 0.000 description 1
125000006278 bromobenzyl group Chemical group 0.000 description 1
239000001110 calcium chloride Substances 0.000 description 1
229910001628 calcium chloride Inorganic materials 0.000 description 1
239000001175 calcium sulphate Substances 0.000 description 1
235000011132 calcium sulphate Nutrition 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
229940023913 cation exchange resins Drugs 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
229940124587 cephalosporin Drugs 0.000 description 1
150000001780 cephalosporins Chemical class 0.000 description 1
239000003610 charcoal Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
229940038649 clavulanate potassium Drugs 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
239000006071 cream Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
238000010908 decantation Methods 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
230000000994 depressogenic effect Effects 0.000 description 1
150000008049 diazo compounds Chemical class 0.000 description 1
BBGKDYHZQOSNMU-UHFFFAOYSA-N dicyclohexano-18-crown-6 Chemical compound O1CCOCCOC2CCCCC2OCCOCCOC2CCCCC21 BBGKDYHZQOSNMU-UHFFFAOYSA-N 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
238000001914 filtration Methods 0.000 description 1
FIMAYKDZLLQUDW-UHFFFAOYSA-N fluoro(dioxido)borane;trimethyloxidanium Chemical compound C[O+](C)C.C[O+](C)C.[O-]B([O-])F FIMAYKDZLLQUDW-UHFFFAOYSA-N 0.000 description 1
238000004019 gradient elution chromatography Methods 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical group 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
239000007788 liquid Substances 0.000 description 1
239000000395 magnesium oxide Substances 0.000 description 1
CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
239000002609 medium Substances 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000006502 nitrobenzyl group Chemical group 0.000 description 1
229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
229920003053 polystyrene-divinylbenzene Polymers 0.000 description 1
235000015320 potassium carbonate Nutrition 0.000 description 1
239000000843 powder Substances 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
238000000746 purification Methods 0.000 description 1
230000005855 radiation Effects 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
239000007921 spray Substances 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
238000001665 trituration Methods 0.000 description 1
JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Cephalosporin Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

CA292,807A 1976-12-11 1977-12-09 Process for the preparation of clavulanic acid esters Expired CA1097653A (en)

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
GB51808/76A GB1589367A (en)	1976-12-11	1976-12-11	Clavulanic acid ethers
GB51808/76		1976-12-12
GB11116/77		1977-03-16
GB1111677		1977-03-16
GB38753/77		1977-09-16
GB3875377		1977-09-16

Publications (1)

Publication Number	Publication Date
CA1097653A true CA1097653A (en)	1981-03-17

Family

ID=27256638

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA292,807A Expired CA1097653A (en)	1976-12-11	1977-12-09	Process for the preparation of clavulanic acid esters

Country Status (14)

Country	Link
JP (1)	JPS5377090A (de)
AR (1)	AR216117A1 (de)
AT (1)	AT356269B (de)
CA (1)	CA1097653A (de)
CH (1)	CH636880A5 (de)
DE (1)	DE2754763A1 (de)
ES (1)	ES464941A1 (de)
FR (1)	FR2373545A1 (de)
GR (1)	GR64001B (de)
IE (1)	IE46436B1 (de)
IL (1)	IL53465A (de)
MX (1)	MX4846E (de)
NL (1)	NL7713644A (de)
NZ (1)	NZ185849A (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0002370B1 (de) *	1977-12-02	1983-05-11	Beecham Group Plc	Verfahren zur Herstellung von Ätherderivaten der Clavulansäure
DE3062347D1 (en) *	1979-08-11	1983-04-21	Beecham Group Plc	Process for the preparation of derivatives of clavulanic acid

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB1573503A (en) *	1975-12-17	1980-08-28	Glaxo Lab Ltd	Clavulanic acid derivatives

1977
- 1977-11-25 IL IL53465A patent/IL53465A/xx unknown
- 1977-12-05 NZ NZ185849A patent/NZ185849A/xx unknown
- 1977-12-07 FR FR7736817A patent/FR2373545A1/fr active Granted
- 1977-12-08 DE DE19772754763 patent/DE2754763A1/de not_active Withdrawn
- 1977-12-09 MX MX776680U patent/MX4846E/es unknown
- 1977-12-09 CA CA292,807A patent/CA1097653A/en not_active Expired
- 1977-12-09 AR AR270306A patent/AR216117A1/es active
- 1977-12-09 NL NL7713644A patent/NL7713644A/xx not_active Application Discontinuation
- 1977-12-09 ES ES464941A patent/ES464941A1/es not_active Expired
- 1977-12-09 JP JP14865677A patent/JPS5377090A/ja active Pending
- 1977-12-09 IE IE2501/77A patent/IE46436B1/en unknown
- 1977-12-09 AT AT881677A patent/AT356269B/de not_active IP Right Cessation
- 1977-12-09 GR GR54946A patent/GR64001B/el unknown
- 1977-12-12 CH CH1523577A patent/CH636880A5/de not_active IP Right Cessation

Also Published As

Publication number	Publication date
MX4846E (es)	1982-10-28
NZ185849A (en)	1980-11-28
GR64001B (en)	1980-01-18
NL7713644A (nl)	1978-06-13
ATA881677A (de)	1979-09-15
IE772501L (en)	1978-06-11
IE46436B1 (en)	1983-06-15
IL53465A (en)	1980-11-30
AR216117A1 (es)	1979-11-30
FR2373545B1 (de)	1982-04-16
ES464941A1 (es)	1979-12-16
DE2754763A1 (de)	1978-06-15
AT356269B (de)	1980-04-25
FR2373545A1 (fr)	1978-07-07
JPS5377090A (en)	1978-07-08
CH636880A5 (en)	1983-06-30
IL53465A0 (en)	1978-01-31

Legal Events

Date	Code	Title	Description
1998-03-17	MKEX	Expiry

Publication	Publication Date	Title
Arimoto et al.	1998	Absolute stereochemistry of halichlorine; a potent inhibitor of VCAM-1 induction
US4966982A (en)	1990-10-30	Process for the production of lactide
SU923365A3 (ru)	1982-04-23	Способ получени простановых производных или их солей
SU633483A3 (ru)	1978-11-15	Способ получени цефалоспориновых производных в виде син-изомера или смеси син- и антиизомеров, или их солей
US4384144A (en)	1983-05-17	Process for preparing cyclopentenone derivatives
EP0118567B1 (de)	1994-03-30	Herstellungsverfahren fuer 2-substituierte cephemabkoemmlinge
CH628902A5 (de)	1982-03-31	Verfahren zur herstellung von 7-beta-(2-oxyimino-2-arylacetamido)-cephalosporinen.
SU1055333A3 (ru)	1983-11-15	Способ получени алкалоидов типа лейрозина или их кислых аддитивных солей
DE2709292A1 (de)	1977-09-08	Verfahren zur herstellung der freien carbonsaeuren in der reihe der cephalosporine und ihrer analogen
EP2004608B1 (de)	2011-09-14	Verbessertes verfahren zur herstellung von montelukast-natrium
US4008229A (en)	1977-02-15	Halo substituted β-lactam antibiotics
DE3783270T2 (de)	1993-04-29	4 halogen-2-oxyimino-3-oxo-buttersaeure.
EP0029202B1 (de)	1983-04-13	Tetrazol-5-thiol-Ester und sie verwendendes Verfahren zur Herstellung von Cephamandol
US3862182A (en)	1975-01-21	Process to prepare novel antibiotic intermediates
SU417944A3 (ru)	1974-02-28	Способ получения алкалоидов
US4316842A (en)	1982-02-23	Penicillin intermediates
US4701534A (en)	1987-10-20	Azetidine derivative
CA1202625A (en)	1986-04-01	Process for the preparation of 5, 11-dihydro-11-[(4- methyl-1-piperazinyl)acetyl]-6h-pyrido[2,3-b] [1,4] benzodiazepin-6-ones
IE46436B1 (en)	1983-06-15	Clavulanic acid ethers
US5097049A (en)	1992-03-17	Process and intermediates for chiral epoxides
KR20050096121A (ko)	2005-10-05	수용성 β-하이드록시니트릴의 제조 방법
GB1589367A (en)	1981-05-13	Clavulanic acid ethers
SU1004382A1 (ru)	1983-03-15	Способ очистки 1,3-пропансультона
FI71562C (fi)	1987-01-19	Foerfarande foer framstaellning av 6- - substituerade penicillansyraderivat och saosom mellanprodukter anvaendbara 6-perfluoralkylsulfonyloxipenicillansyraderivat.
CA1152999A (en)	1983-08-30	Process for the preparation of derivatives of clavulanic acid